Cerebral ischemia/reperfusion injury is one of the main causes of neuronal damage. Neuron ferroptosis and microglia polarization are considered as critical processes during cerebral ischemia/reperfusion. Adipocyte enhancer‐binding protein 1 (AEBP1) usually acts as a transcriptional repressor which is involved in various diseases. However, it is still remains unknown whether AEBP1 could have important roles in regulating the neuron ferroptosis and microglia polarization in cerebral ischemia/reperfusion injury. The oxygen‐glucose deprivation and reperfusion (OGD/R)‐treated cells and middle cerebral artery occlusion (MCAO)‐treated mice were used as in vitro and in vivo models. The differentially expressed factors were analyzed according to GEO datasets. Relative mRNA and protein expression levels were detected by qRT‐PCR and western blot analysis. Cell viability was measured by CCK‐8 assay. ROS, GSH and iron contents were detected using specifical assay kits. CD26 and CD206 levels were measured by immunofluorescence assay. Inflammatory cytokines were detected by ELISA. The association between AEBP1 and PRKCA was assessed by luciferase reporter and ChIP analyses. The neuron damage in mice was analyzed by TTC staining and neurological deficit score. Transcription factor AEBP1 was increased in OGD/R‐treated HT22 and BV2 cells. AEBP1 silencing attenuated OGD/R‐induced HT22 cell ferroptosis through increasing cell viability, GSH and GPX4 levels, and decreasing ROS, iron and ACSL4 levels. AEBP1 knockdown promoted microglia M2 polarization by increasing CD206‐positive cells and Arg‐1 level, and reducing iNOS, TNF‐α, IL‐1β and IL‐6 levels in BV2 cells. AEBP1 transcriptionally repressed PRKCA expression, and further regulated PI3K/Akt signaling activation. Inhibition of PRKCA or PI3K/Akt reversed the effects of AEBP1 silencing on neuron ferroptosis and microglia M2 polarization. AEBP1 downregulation attenuated neuronal damage by decreasing infarct size and deficit scores in MCAO‐treated mice. AEBP1 silencing mitigated neuron ferroptosis and promoted microglia M2 polarization through increasing PRKCA and activating PI3K/Akt signaling, indicating the potentially protective action of AEBP1 knockdown in cerebral ischemia/reperfusion injury.
